Finding Our Way in the Dark Proteome
Open accessAbstract
The traditional structure-function paradigm has provided significant insights for well-folded proteins in which structures can be easily and rapidly revealed by X-ray crystallography beamlines. However, approximately one-third of the human proteome is comprised of intrinsically disordered proteins and regions (IDPs/IDRs) that do not adopt a dominant well-folded structure, and therefore remain "unseen" by traditional structural biology methods. This Perspective considers the challenges raised by the "Dark Proteome", in which determining the diverse conformational substates of IDPs in their free states, in encounter complexes of bound states, and in complexes retaining significant disorder requires an unprecedented level of integration of multiple and complementary solution-based experiments that are analyzed with state-of-the art molecular simulation, Bayesian probabilistic models, and high-throughput computation. We envision how these diverse experimental and computational tools can work together through formation of a "computational beamline" that will allow key functional features to be identified in IDP structural ensembles.
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Research works printed but not linked: 2
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- Authors
- Bhowmick, A., Brookes, D. H., Yost, S. R., Dyson, H. J., Forman-Kay, J. D., Gunter, D., Head-Gordon, M., Hura, G. L., Pande, V. S., Wemmer, D. E., Wright, P. E., & Head-Gordon, T.
- Affiliations
- University of California, Berkeley (US)
- Scripps Research Institute (US)
- University of Toronto (CA)
- Stanford University (US)
- Lawrence Berkeley National Laboratory (US)
- Corresponding author
- Forman-Kay, Julie D.
- Head-Gordon, Teresa
- ORCID
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-07-19
- Volume
- 138
- Issue
- 31
- Pages
- 9730-9742
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC5051545
- OpenAlex
- W2470406062
- Cited by
- 128
- References
- 176
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 10 · 2021: 15 · 2020: 14 · 2019: 26 · 2018: 23 · 2017: 20 · 2016: 1
- FWCI
- 12.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Division of Chemistry (CHE-1363320)
- National Cancer Institute (CA96865)
- Canada Research Chairs
- Natural Sciences and Engineering Research Council of Canada (RGPIN-2016-06718)
- National Institute of General Medical Sciences (GM113251)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Physical Sciences › Chemistry › Spectroscopy › Advanced NMR Techniques and Applications
- Keywords
- intrinsically disordered proteins, intrinsically disordered regions, dark proteome, protein conformational ensembles, solution structure determination, Bayesian probabilistic model, molecular simulation, protein function
- MeSH terms
- Bayes Theorem, Chromatography, Gel, Humans, Kinetics, Magnetic Resonance Spectroscopy, Probability, Protein Conformation, Software, Genome, Human, Protein Folding, Crystallography, X-Ray, Computational Biology, Proteome, Proteomics, Molecular Dynamics Simulation, Intrinsically Disordered Proteins
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